Sickle cell disease is an autosomal recessive disorder and the most common monogenic genetic disease in the United States. Mortality in sickle cell patients with elevated pulmonary pressures is believed to be significantly increased as compared to those with normal pulmonary pressures. We have enrolled 659 subjects and 103 controls in a study of the prevalence and prognosis of subjects with sickle cell disease and suspected pulmonary hypertension. All subjects were screened with transthoracic echocardiograms and the tricuspid regurgitant jet velocity (TRV) used to estimate the pulmonary artery systolic pressure. Suspected pulmonary hypertension was prospectively defined by a TRV >= 2.5 m/sec and severe pulmonary hypertension defined by a TRV >= 3.0 m/sec. Subjects have been followed for a mean of 6 years and censored at time of death or loss to follow-up. We have analyzed Doppler echocardiographic assessments of pulmonary systolic pressure in 529 consecutive patients (mean age=33.0 years). Doppler-defined elevation of the TRV occurred in 31 percent of patients. Diastolic dysfunction was present in 18% of patients. A combination of diastolic dysfunction and TRV elevation was present in 11% of patients, and diastolic dysfunction accounted for only 10% to 20% of the variability in TR jet velocity. Diastolic dysfunction, as reflected by a low E/A ratio, was associated with mortality with a risk ratio of 3.5 (95% confidence interval 1.5 to 8.4, p<0.001), even after adjustment for TR jet velocity. The presence of both diastolic dysfunction and pulmonary hypertension conferred a risk ratio for death of 12.0 (95% confidence interval 3.8 to 38.1, p <0.001). Right heart catheterization was performed under a separate protocol in most patients with TRV >= 2.8 m/sec (based on the results of the screening echo). Based on these data, 60% of patients with sickle cell disease have elevated pulmonary artery systolic pressures (TRV >= 2.8 m/sec) and 9% have severely elevated pressures. Multiple-regression analysis identified increasing age, increased serum biomarkers (LDH, total bilirubin) and arginine/ornithine ratio as significant independent predictors of elevation of pulmonary pressures. Fetal hemoglobin levels did not predict pulmonary artery pressure elevation nor did a history of hydroxyurea treatment. Left ventricular dysfunction was rarely observed (<2% of patients). The patients diagnosed with pulmonary hypertension had significantly greater mortality. These studies suggest that secondary pulmonary hypertension is common in adult patients with sickle cell disease, appears to have no association with hydroxyurea therapy, while there are positive associations with biomarkers suggestive of hemolysis and with earlier mortality. These data suggest that all patients should be screened for this complication and those with elevated pressures documented by right heart catheterization should be considered for therapeutic trials with oxygen, anticoagulation, transfusion and/or selective pulmonary vasodilators. There have been 72 new subjects enrolled at the NIH during this year;16 were controls and 56 were subjects with sickle cell disease. There were no new subjects enrolled at the Howard University site. Total enrolled at Howard University is 131 and the total enrolled at NIH is 696. Total enrollment for all sites is 827. Subjects continue to be enrolled in this trial and referred for treatment studies available at NIH. We are conducting 2, 4, 6, 8 and 10 year follow-up visits for comprehensive data collection. We also completed comprehensive survival update on all subjects enrolled to date. Our objective is to recruit at least 1000 subjects with sickle cell disease as an initial discovery cohort for exploratory genetic studies. This will allow for sufficient statistical power to preliminarily identify genetic modifiers and prognostic clinical factors. As part of this protocol, adult patients were assessed for depression using the Beck Depression Inventory II (BDI-II). The findings of these tests suggest that there is a correlation between severity of depressive symptoms and reported sleep quality. Further planned analysis will look to elucidate the nature of this correlation and examine the association of severity of depressive symptoms and pain scores, reliance on analgesics, measures of treatment adherence, and genetic factors. These findings suggest that screening and treatment of depression are important components of routine care for sickle cell disease. Sample analysis from this protocol found that ET-1 appears to be a mediator of elevated pulmonary artery pressures as estimated by echocardiography in patients with SCD. This finding lends support to clinical efficacy of the ET-1 receptor antagonists bosentan and ambrisentan in SCD adults with PH and identified erythrocyte arginase release as a significant contributing factor to PH severity and patient mortality in SCD. However, decreased Arg bioavailability and a shift of metabolism towards ornithine-dependent pathways are novel mechanisms that play a role in PH of various etiologies. Vaso-occlusive pain crises resulting in hospitalization is another phenotype of sickle cell anemia, and like elevated pulmonary pressures, frequent severe pain events are another risk factor for early mortality. It is unclear if this association between frequent pain and mortality is still relevant since the institution of modern therapies. Accordingly, the epidemiology of severe acute pain crises resulting in hospitalization has been reviewed in this cohort. One quarter of subjects with sickle cell anemia are not frequently hospitalized for pain (<1 per year), and more frequent pain crises are independently associated with higher hematocrit, ferritin, and HDL cholesterol. Despite modern therapy for sickle cell anemia, more frequent pain crises remain a risk factor for early mortality. This mortality risk is independent of the previously described risk of death with an elevated TRV on echocardiogram, elevated ferritin or lower glomerular filtration rate. Thus, pain crises requiring hospital based treatment is a clinically meaningful prognostic measure along with tricuspid regurgitation, ferritin and renal function due their cumulative association with premature death.

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